5-oxo-2-pyrrolidinepropanoic acid derivatives and use as cognition activators

ABSTRACT

5-Oxo-2-pyrrolidinepropanoic acids, base addition salts, esters and amides are useful as agents for the reversal of amnesia. Pharmaceutical compositions containing said compounds and methods for using said compositions for treating senility and reversal of amnesia are also taught.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 476,524, filedMar. 24, 1983, now U.S. Pat. No. 4,559,358 issued Dec. 17, 1985 which inturn is a continuation-in-part of application Ser. No. 381,662 filed May24, 1982, now abandoned.

BACKGROUND OF THE INVENTION

The synthesis of 5-oxo-2-pyrrolidinepropanoic acid then known aspyrrolidin-2-one-5-propanoic acid is reported in Chem. Ber., 88, 509(1955). The synthesis of pyrrolidin-2-one-5-propanoic acid methyl esteris reported in J. Am. Chem. Soc., 69, 690 (1947). The synthesis ofpyrrolidin-2-one-5-propanoic acid ethyl ester is reported in Coll.Czech. Chem. Comm., 12, 278 (1947). Pyrrolidin-2-one-5-propanoic acidamide is reported in Chem. Ber., 55B, 3950-3960 (1922) and thepiperidide of pyrrolidin-2-one-5-propanoic acid is reported in Ann.,581, 225-237 (1953). The compounds are utilized in the references aschemical intermediates or as crystalline derivatives.

SUMMARY OF THE INVENTION

The invention sought to be patented in its generic chemical compoundaspect is a compound having the structural formula I ##STR1## wherein Ris O-- as a salt with a pharmaceutically acceptable metal or aminecation; ##STR2## wherein X is hydrogen, alkyl of from one to six carbonatoms, alkoxy of from one to six carbon atoms, halo or trifluoromethyl;O-alkyl having 3, 4, 5, or 6 carbon atoms; or NR₁ R₂ wherein R₁ is alkylof from one to six carbon atoms or alkyl of from two to six carbon atomssubstituted by amino, alkylamino, or dialkylamino in which alkylcontains one to six carbon atoms, hydroxy, or alkoxy of from one to sixcarbon atoms, mercapto, or alkylmercapto of from one to six carbonatoms; 5- or 6-membered cycloalkyl; 5- or 6-membered cycloalkylsubstituted by alkyl of from one to four carbon atoms, phenyl, or phenylsubstituted by alkyl of from one to four carbon atoms, or a 5- or6-membered heterocyclic group containing up to four heteroatomsconsisting of nitrogen, oxygen, and sulfur which may be substituted byamino, alkylamino, dialkylamino, or alkyl of from one to four carbonatoms; R₂ is hydrogen or alkyl of from one to six carbon atoms, or whereR₁ R₂ combine with N to form 2,6-dimethylpiperidine.

In a second generic aspect, the invention sought is a compound havingthe structural formula I, wherein R is O-- as a salt with apharmaceutically acceptable metal or amine cation; ##STR3## wherein X ishydrogen, alkyl of from one to six carbon atoms, alkoxy of from one tosix carbon atoms, halo, or trifluoromethyl; or O-alkyl having 3, 4, 5,or 6 carbon atoms; or NR₁ R₂ wherein R₂ is hydrogen, and R₁ is alkyl offrom one to six carbon atoms, or alkyl of from two to six carbon atomssubstituted by amino, alkylamino, or dialkylamino in which alkylcontains one to six carbon atoms; 2,6-dimethylphenyl,4-amino-3-pyridinyl, 3-amino-4-pyridinyl, 4-pyridinyl, or 5-tetrazol-yl;or where R₁ R₂ combine with N to form 2,6-dimethylpiperidine.

The invention sought to be patented in its first specific chemicalcompound aspect are the compounds having the names:

5-oxo-2-pyrrolidinepropanoic acid benzyl ester;

5-oxo-2-pyrrolidinepropanoic acid N-benzyl amide;

5-oxo-2-pyrrolidinepropanoic acid N-N',N'-diisopropylaminoethyl amide;

5-oxo-2-pyrrolidinepropanoic acid N-(L)α-methylbenzyl amide;

5-oxo-2-pyrrolidinepropanoic acid N-4-(aminopyridinyl)amide;

5-oxo-2-pyrrolidinepropanoic acid N-(2,6-dimethylphenyl)amide;

5-oxo-2-pyrrolidinepropanoic acid 4-(3-aminopyridinyl)amide, and

5-oxo-2-pyrrolidinepropanoic acid 3-(4-aminopyridinyl)amide.

The invention sought to be patented in its pharmaceutical compositionaspect is a composition which comprises a compound having the structuralformula II ##STR4## wherein R₄ is OH; O-- as a salt with apharmaceutically acceptable metal or amine cation; ##STR5## wherein X ishydrogen, alkyl of from one to six carbon atoms, alkoxy of from one tosix carbon atoms, halo or trifluoromethyl; --O--alkyl having from one tosix carbon atoms, or NR₁ 'R₂ wherein R₁ ' is hydrogen, alkyl of from oneto six carbon atoms or alkyl of from two to six carbon atoms substitutedby amino, alkylamino, or dialkylamino in which alkyl contains one to sixcarbon atoms, hydroxy or alkoxy of from one to six carbon atoms,mercapto or alkylmercapto of from one to six carbon atoms; 5- or6-membered cycloalkyl, 5- or 6-membered cycloalkyl substituted by alkylof from one to four carbon atoms; phenyl or phenyl substituted by alkylof from one to four carbon atoms or a 5- or 6-membered heterocyclicgroup containing up to four heteroatoms consisting of nitrogen, oxygenand sulfur which may be substituted by amino, alkylamino, dialkylamino,or alkyl of from one to four carbon atoms; R₂ is hydrogen or alkyl offrom one to six carbon atoms, or where R₁ 'R₂ combine with N to form2,6-dimethylpiperidine in combination with a pharmaceutically acceptablecarrier.

The invention sought to be patented in its first specific pharmaceuticalcomposition aspect is a compound which comprises5-oxo-2-pyrrolidinepropanoic acid, in combination with apharmaceutically acceptable carrier.

The invention sought to be patented in a second specific pharmaceuticalcomposition aspect is a composition which comprises5-oxo-2-pyrrolidinepropanoic acid ethyl ester in combination with apharmaceutically acceptable carrier.

The invention sought to be patented in a third specific pharmaceuticalcomposition aspect is a composition which comprises5-oxo-2-pyrrolidinepropanoic acid amide in combination with apharmaceutically acceptable carrier.

The invention sought to be patented in its pharmaceutical method aspectis a method for treating senility or for reversing amnesia, which methodcomprises administering an effective amount of the above definedpharmaceutical compositions to a mammal in need thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The esters, salts, and amides of the invention may be readily preparedfrom 5-oxo-2-pyrrolidinepropanoic acid by standard methods. Thesynthesis of this acid is reported in Coll. Czech. Chem. Comm., 12, 278(1947). Thus, the acid may be converted to additional compounds havingstructural formula I, i.e., salts, esters and amides, by standardprocedures. For example, the salts may be prepared by treating the acidwith an equivalent amount of a suitable base. The esters and amides maybe prepared by first converting the acid to an acid halide such as theacid chloride with, for example, thionyl chloride. The so produced acidchloride may then be treated with the desired alcohol or amine,preferably in the presence of a suitable acid acceptor such astriethylamine or pyridine.

The compounds of the invention may also be prepared in an alternatepreferred method, which comprises treating the compound havingstructural formula III with at least an approximate equal molar amountof an alcohol or amine to produce respectively an ester or amide.##STR6##

The synthesis of esters is conducted preferably in the presence of anacid catalyst such as a trace of hydrogen chloride, hydrogen bromide, orother strong acid. The reactants may be present in equimolar amountsalthough the use of water or desired alcohol in excess as the solvent ispreferred.

The amides are directly prepared with an equimolar amount of the desiredamine in a relatively inert or slower reacting solvent such as analcohol or acetonitrile.

The reaction is carried out at a temperature of 25° C. to 100° C. forperiods of from one to 96 hours, preferably at the boiling point of thesolvent or to 150° C. Sufficient time should be allowed to effectcomplete reaction of starting material III for easier purification.

The product may be isolated by crystallization, chromatography or as abase addition salt by suitable adjustment of pH in the case of the freeacid.

The necessary starting material, III, is a known compound synthesized inthe following references: J. Amer. Chem. Soc., 69, 690-692 (1947); Coll.Czech. Chem. Comm., 12, 278-291 (1947); and Chem. Ber., 88, 509-510(1955).

The pharmaceutically-acceptable salts of the acid are prepared by forexample, suspending the acid in water and adjusting the pH with thepharmaceutically-acceptable base, or by reacting the compound of formulaIII with one equivalent of the pharmaceutically acceptable base in asolvent and removing the solvent under reduced pressure.

Pharmaceutically acceptable bases are organic and inorganic bases.Examples of suitable inorganic bases for salt formation are sodiumhydroxide, potassium hydroxide, sodium carbonate, calcium carbonate,potassium carbonate, sodium bicarbonate, and the like.

The term pharmaceutically acceptable amine cation contemplates thepositively charged ammonium ion and analogous ions derived from organicnitrogenous bases strong enough to form such cations. Bases useful forthe purpose of forming pharmacologically-acceptable nontoxic additionsalts of such compounds containing free carboxyl groups form a classwhose limits are readily understood by those skilled in the art. Merelyfor illustration, they can be said to comprise, in cationic form, thoseof the formula: ##STR7## wherein R_(a), R_(b), and R_(c), independently,are hydrogen, alkyl of from about one to about six carbon atoms,cycloalkyl of from about three to about six carbon atoms, aryl of aboutsix carbon atoms, aralkyl of from about 7 to about 11 carbon atoms,hydroxyalkyl of from about two to about four carbon atoms, ormonoarylhydroxyalkyl of from about 8 to about 15 carbon atoms, or, whentaken together with the nitrogen atom to which they are attached, anytwo of R_(a), R_(b), and R_(c) may form part of a 5 to 6-memberedheterocyclic ring containing carbon, hydrogen, oxygen, or nitrogen, saidheterocyclic rings and said aryl groups being unsubstituted or mono- ordialkyl substituted said alkyl groups containing from about one to aboutsix carbon atoms. Illustrative therefore of R_(a), R_(b), and R_(c)groups comprising pharmacologically-acceptable cations derived fromammonia or a basic amine are ammonium, mono-, di-, andtrimethylammonium, mono-, di- and triethylammonium, mono-, di-, andtripropylammonium (iso and normal), ethyldimethylammonium,benzyldimethylammonium, cyclohexylammonium, benzylammonium,dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidine, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium,2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- andtriethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium,tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, and thelike.

The term, pharmaceutically acceptable metal cation contemplates thepositively charged ions derived from such metals as sodium, potassium,calcium, magnesium, aluminum, zinc, iron, and the like. The salts areprepared by contacting the free form of the compound with an equivalentamount of the desired base in the conventional manner. The free formsmay be regenerated by treating the salt form with an acid. For example,dilute aqueous acid solutions may be utilized to regenerate the freeform from a respective salt. Dilute aqueous hydrochloric acid issuitable for this purpose. The free forms differ from their respectivesalt forms somewhat in certain physical properties such as solubility inpolar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purpose of the invention.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, with pharmaceutically acceptable solvents such as water, ethanol,and the like are equivalent to the unsolvated forms for purposes of theinvention.

The alkyl groups contemplated by the invention unless otherwise stated,comprise both straight and branched carbon chains of from one to aboutsix carbon atoms. Representative of such groups are methyl, ethyl,isopropyl, pentyl, 3-methylpentyl, and the like.

The compounds of the invention contain an asymmetric carbon atoms whichis the 2-position carbon atom of the ring marked with an asterisk. Theinvention contemplates the pure S isomer, the pure R isomer and mixturesthereof including the racemic mixture. ##STR8##

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 or 10 toabout 70 percent of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions.As an example may be mentioned water or water propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by dissolving the active componentin water and adding suitable colorants, flavors, stabilizing andthickening agents as desired. Aqueous suspensions suitable for oral usecan be made by dispersing the finely divided active component in waterwith viscous material, i.e., natural or synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose, and other well-knownsuspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternately, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon, or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e., under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents, and the like. The liquid utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol, and the like as well as mixturesthereof. Naturally, the liquid utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities orpreparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 500 mg preferably to 5 to 100 mgaccording to the particular application and the potency of the activeingredient. The compositions can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as cognition activators, the mammalian dosage rangefor a 70 kg subject is from 1 to 1500 mg/kg of body weight per day orpreferably 25 to 750 mg/kg of body weight per day. The dosages, however,may be varied depending upon the requirements of the patient, theseverity of the condition being treated, and the compound beingemployed. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter the dosage is increased by small increments until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The effectiveness of the aforementioned compounds was determined by thetest designed to show the compound's ability to reverse amnesia producedby electroconvulsive shock. The test is fully described in U.S. Pat. No.4,145,347, issued Mar. 20, 1979, and is herein incorporated byreference. The test compounds in the present instance were administeredorally and the length of the electroconvulsive shock being 1.0 second.

The following criteria are used in interpreting the percent of amnesiareversal scores: 40 percent or more (active=A) 25 to 39 percent(borderline=C) and 0 to 24 percent (inactive=N).

Table 1 below reports the percent of amnesia reversal of orallyadministered 5-oxo-2-pyrrolidinepropanoic acid.

                  TABLE 1                                                         ______________________________________                                        Dose mg/kg                                                                             0.63    1.25    2.50  5.00  20.00 80.00                              ______________________________________                                        % Reversal                                                                             58      83      91    89    100   67                                 Rating   A       A       A     A     A     A                                  ______________________________________                                    

Table 2 below reports the percent of amnesia reversal of orallyadministered 5-oxo-2-pyrrolidinepropanoic acid esters.

                  TABLE 2                                                         ______________________________________                                         ##STR9##                                                                     R Group    Dose mg/kg                                                         of Esters  0.63   1.25   2.50 5.00  20.00  80.00                              ______________________________________                                        % Reversal                                                                    (Rating)                                                                      OCH.sub.3                     75(A) 100(A) 75(A)                              OCH.sub.2 C.sub.6 H.sub.5                                                                44     56     67   64(A) 64(A)  71(A)                                         (A)    (A)    (A)                                                  OCH.sub.2 C.sub.6 H.sub.4 -p-Cl                                                                             25(C)  0(N)  42(A)                              ______________________________________                                    

Table 3 below reports the percent of amnesia reversal of orallyadministered 5-oxo-2-pyrrolidine propanoic acid amides.

                                      TABLE 3                                     __________________________________________________________________________                   Dose                                                           R.sub.1      R.sub.2                                                                         mg/kg                                                                             1.0 5.0 10.0                                                                              20.0                                                                              80.0                                                                              100                                    __________________________________________________________________________    H            H     64(A)   33(C)       64(A)                                   ##STR10##   H     45(A)   54(A)       22(N)                                   ##STR11##   H         50(A) 0(N)                                                                            8(N) 62(A)                                                                        58(A) 50(A)                                 ##STR12##   H     100(A) 64(A) 64(A)                                                                    100(A) 59(A) 48(A)                                                                        100(A) 53(A) 48(A)                     CH.sub.2 CH.sub.2 N[CH(CH.sub.3).sub.2 ].sub.2                                             H     17(N)                                                                             33(C)       17(N)                                      __________________________________________________________________________     a. Also tested at 0.1, 0.01, and 0.001 mg/kg with the following results       respectively: 0(N), 28(C) and 71(A).                                     

CHEMICAL COMPOSITIONS Example A Preparation of5-Oxo-2-pyrrolidinepropanoic acid

A suspension (partial solution) of 25 g ofdihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) in 150 ml of deionizedwater is treated with 0.1 ml of concentrated hydrochloric acid. Themixture is heated to reflux (100° C.) for 80 hours. Charcoal (0.5 g) isadded and the mixture is filtered through filter aid. The solution isconcentrated at reduced pressure, the 5-oxo-2-pyrrolidinepropanoic acidcrystallizes and is isolated by filtration. After drying in vacuo the5-oxo-2-pyrrolidinepropanoic acid has a melting point of 125°-127° C.

Example B Preparation of 5-oxo-2-pyrrolidinepropanoic acid benzyl ester

Twenty-eight grams of dihydro-1H-pyrrolizine-3,5 (2H,6H)-dione (III) aredissolved in 76 g of benzyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at 98° C. for 104hours. The mixture is cooled and excess benzyl alcohol is distilled at0.1 mm pressure to a maximum bath temperature of 100° C. The residualoil is dissolved in 1 l of anhydrous diethylether, 1 g of activatedcharcoal is added and the resulting suspension is filtered throughfilter aid. The filtrate is concentrated at reduced pressure and theresulting crystals are isolated by filtration. Recrystallization fromcyclohexane containing 12% methylene chloride yields5-oxo-2-pyrrolidinepropanoic acid benzyl ester with a melting point of79°-80° C.

Example C Preparation of 5-oxo-2-pyrrolidinepropanoic acid methyl ester

Twenty-eight grams of dihydro-1H-pyrrolizine-3,5 (2H,6H)-dione (III) aredissolved in 100 g of methyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at reflux for 104hours. The mixture is cooled and excess methyl alcohol is distilled atreduced pressure. The residual oil is dissolved in 1 l of anhydrousdiethylether, 1 g of activated charcoal is added and the resultingsuspension is filtered through filter aid. The filtrate is concentratedat reduced pressure and the resulting crystals are isolated byfiltration. Recrystallization from methanol yields5-oxo-2-pyrrolidinepropanoic acid methyl ester with a melting point of52°-53° C.

Example D Preparation of 5-oxo-2-pyrrolidinepropanoic acid ethyl ester

Twenty-eight grams of dihydro-1H-pyrrolizine-3,5 (2H,6H)-dione (III) aredissolved in 100 g of ethyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at reflux for 104hours. The mixture is cooled and excess ethyl alcohol is distilled atreduced pressure. The oil is dissolved in 1 l of anhydrous diethylether,1 g of activated charcoal is added and the resulting suspension isfiltered through filter aid. The filtrate is concentrated at reducedpressure and the resulting crystals are isolated by filtration.Recrystallization from carbon tetrachloride-petroleum ether yields5-oxo-2-pyrrolidinepropanoic acid ethyl ester with a melting point of60°-61° C.

Example E Preparation of 5-oxo-2-pyrrolidinepropanoic acido-chlorobenzyl ester

Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) aredissolved in 31 g of o-chlorobenzyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at 100° C. for 71hours. The mixture is cooled and dissolved in 150 ml of anhydrousdiethylether. The solution is cooled to induce crystallization and theresulting crystals are isolated by filtration. Recrystallization fromtoluene-diethyl ether yields 5-oxo-2-pyrrolidinepropanoic acido-chlorobenzyl ester with a melting point of 99°-100° C.

Example F Preparation of 5-oxo-2-pyrrolidinepropanoic acidm-chlorobenzyl ester

Two hundred and eighty eight milligrams ofdihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) are dissolved in 600 mg ofm-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid isadded. The solution is heated at 100° C. for 40 hours. The mixture iscooled and is dissolved in 50 ml of anhydrous diethylether. The filtrateis cooled to induce crystallization and the resulting crystals areisolated by filtration. Recrystallization from toluene-petroleum etheryields 5-oxo-2-pyrrolidinepropanoic acid m-chlorobenzyl ester with amelting point of 90°-91° C.

Example G Preparation of 5-oxo-2-pyrrolidinepropanoic acidp-chlorobenzyl ester

Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H) -dione (III) aredissolved in 31 g of p-chlorobenzyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at 100° C. for 65hours. The mixture is cooled and chromatographed over silica gel indichloromethane. The starting p-chlorobenzyl alcohol is eluted withdichloromethane and the product is eluted with 2.5% methanol indichloromethane. The eluate containing the product is concentrated atreduce pressure and the residual oil solidifies upon standing. The solidis recrystallized from toluene diethyl ether to yield5-oxo-2-pyrrolidinepropanoic acid p-chlorobenzyl ester with a meltingpoint of 63°-64° C.

Example H Preparation of 5-oxo-2-pyrrolidinepropanoic acidp-trifluoromethylbenzyl ester

Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) aredissolved in 29 g of benzyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at 100° C. for 72hours. The mixture is cooled and chromatographed over silica gel indichloromethane. The starting p-trifluoromethylbenzyl alcohol is elutedwith dichloromethane and the product is eluted with 1.0% methanol indichloromethane. The eluate containing the product is concentrated atreduced pressure and the residual oil solidifies upon standing. Thesolid is recrystallized from toluenediethyl ether to yield5-oxo-2-pyrrolidinepropanoic acid p-trifluoromethylbenzyl ester with amelting point of 81°-82° C.

Example I Preparation of 5-oxo-2-pyrrolidinepropanoic acidp-methylbenzyl ester

Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) aredissolved in 27 g of p-methylbenzyl alcohol and 0.2 ml of concentratedhydrochloric acid is added. The solution is heated at 100° C. for 48hours. The mixture is cooled and chromatographed over silica gel indichloromethane. The starting p-methylbenzyl alcohol is eluted withdichloromethane and the product is eluted with 1.0% methanol indichloromethane. The eluate containing the product is concentrated atreduced pressure and the residual oil solidifies upon standing. Thesolid is recrystallized from toluene-diethyl ether to yield5-oxo-2-pyrrolidinepropanoic acid p-methylbenzyl ester with a meltingpoint of 71°-72° C.

Example J Preparation of 5-oxo-2-pyrrolidinepropanoic acid amide

A solution of 7.0 g (0.5 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine in 100 ml of ethanol issaturated with anhydrous ammonia and is allowed to stand for 48 hours.The solution is evaporated and the residue after two recrystallizationsfrom n-butanol yields 5-oxo-2-pyrrolidinepropanoic acid amide with amelting point of 177.5°-178° C.

Example K Preparation of 5-oxo-2-pyrrolidinepropanoic acid N-benzylamide

A solution of 7.0 g (0.05 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine in 50 ml of ethanol is treatedwith 5.4 g (0.5 mol) of benzyl amine. The mixture is refluxed for 48hours and is concentrated at reduced pressure.

The residue is chromatographed over silica gel in chloroform, followedby elution with 5% methanol in chloroform. After concentration atreduced pressure, 5-oxo-2-pyrrolidinepropanoic acid N-benzyl amide has amelting point of 140°-142° C.

Example L Preparation of 5-oxo-2-pyrrolidinepropanoic acidN-N',N'-diisopropylaminoethyl Amide

A solution of 7.0 g (0.05 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine in 50 ml of ethanol is treatedwith 7.2 g (0.05 mol) of N-N',N'-diisopropylaminoethylamine.

The mixture is refluxed for 24 hours and is concentrated at reducedpressure. The residue is chromatographed over silica gel in methanol andconcentrated at reduced pressure. The residue is dissolved in anhydrousdiethyl ether, charcoaled and cooled to dry ice temperatures. Thecrystals of 5-oxo-2-pyrrolidinepropanoic acidN-N',N'-diisopropylaminoethyl amide are isolated by filtration and afterdrying in a vacuum oven have a melting point of 62°-65° C.

Example M Preparation of 5-oxo-2-pyrrolidinepropanoic acidN-(L)alpha-methylbenzyl amide

A mixture of 7.0 g (0.05 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine and 8.4 g (0.07 mol)L-alpha-methylbenzylamine is heated at 110° C. for 16 hours and at 160°C. for 24 hours. The residue is heated at reduced pressure and uponcooling melts at 100°-107° C. Chromatography of the residue over silicagel and elution with 5% methanol in methylene chloride yields5-oxo-2-pyrrolidinepropanoic acid N-(L)-alpha-methylbenzyl amide with amelting point of 108°-112° C.

Example N Preparation of 5-oxo-2-pyrrolidinepropanoic acidN-(4-pyridinyl) amide

A mixture of 1.5 g (0.0108 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine and 1.14 g (0.012 mol) of4-aminopyridine is heated at 150° C. for 24 hours. The residue has amelting point of 180°-184° C. The residue is chromatographed over silicagel using 10% methanol in methylene chloride for elution. Afterrecrystallization from acetonitrile the crystalline5-oxo-2-pyrrolidinepropanoic acid N-(4-pyridinyl) amide has a meltingpoint of 187°-188° C.

Example O Preparation of 5-oxo-2-pyrrolidine-propanoic acidN-(2,6-dimethylphenyl) amide

A mixture of 7.0 g (0.05 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine and 13.3 g (0.11 mol) of2,6-dimethylaniline is heated at 140° C., for 72 hours. The residue iscrushed and extracted with boiling dichloromethane. The residue isrecrystallized from a 1:1 mixture of isopropanol and methanol to yield5-oxo-2-pyrrolidinepropanoic acid N-(2,6-dimethylphenyl) amide with amelting point of 206°-208° C.

Example P Preparation of 5-oxo-2-pyrrolidinepropanoic acidN-4-(3-nitro-1-oxide-pyridinyl) Amide

A mixture of 7.0 g (0.05 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine and 7.3 g (0.05 mol) of4-amino-3-nitro-pyridine-1-oxide (Synthesized as in Chem. Pharm. Bull.(Tokyo) 12, 866-872 (1964), Chem. Abstr., 61, 14661a (1964)) is heatedat 160° C. for 18 hours, and the residue is recrystallized fromacetonitrile to afford crystalline 5-oxo-2-pyrrolidinepropanoic acidN-4-(3-nitro-1-oxide-pyridinyl) amide.

Example Q Preparation of 5-oxo-2-pyrrolidinepropanoic acid4-(3-aminopyridinyl) amide

A solution of 14.3 g (0.05 mol) of 5-oxo-2-pyrrolidinepropanoic acidN-4-(3-nitro-1-oxidepyridinyl) amide in 200 ml of ethanol is treatedwith hydrogen in the presence of Raney Nickel catalyst. The mixture isfiltered and concentrated to yield 5-oxo-2-pyrrolidinepropanoic acid4-(3-aminopyridinyl) amide.

Example R Preparation of 5-oxo-2-pyrrolidinepropanoic acidN-3-(4-nitro-1-oxide-pyridinyl) amide

A mixture of 7.0 g (0.05 mol) ofdihydro-1H-3,5-(2H,6H)dioxopyrrolizidine and 7.3 g (0.05 mol) of3-amino-4-nitro-pyridine-1-oxide (Synthesized as in Roczniki Chem., 38,777-784 (1964), Chem Abstr., 61, 10653c (1964)) is heated at 160° C. for18 hours. The residue is recrystallized from acetonitrile to affordcrystalline 5-oxo-2-pyrrolidinepropanoic acidN-3-(4-nitro-1-oxide-pyridinyl) amide.

Example S Preparation of 5-oxo-2-pyrrolidinepropanoic acid3-(4-aminopyridinyl) amide

A solution of 14.3 g (0.05 mol) of 5-oxo-pyrrolidin-2-propanoic acidN-3-(4-nitro-1-oxidepyridinyl) amide in 200 ml of ethanol is treatedwith hydrogen in the presence of Raney Nickel catalyst. The mixture isfiltered and concentrated to yield 5-oxo-2-pyrrolidinepropanoic acid3-(4-aminopyridinyl) amide.

The invention is further illustrated by the following Examples oftablets containing 1.0, 2.5, 25, 50 mg; capsules containing 1.0, 2.5,25, 50 mg respectively of active ingredient, an example of a parenteralformulation, an example of a Rectal Suppository formulation, an exampleof a Suspension formulation and an example of a Syrup forReconstitution.

PHARMACEUTICAL COMPOSITIONS Example 1

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      150    g                                             Lactose                  1124   g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid, lactose, and hydroxypropylcellulose are blended and granulated with 50:50 ethanol-water. The wetgranulation is screened, dried, and rescreened. The resulting driedgranulation is blended with magnesium stearate and the corn starch andthe mixture is compressed into 225 mg tablets using an 11/32 inchstandard concave punch. Yield equals approximately 6000 tablets eachcontaining 25.0 mg of 5-oxo-2-pyrrolidinepropanoic acid.

Example 2

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      15     g                                             Lactose                  1249   g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid, lactose, and hydroxypropylcellulose are blended and granulated with 50:50 ethanol-water. The wetgranulation is screened, dried, and rescreened. The resulting driedgranulation is blended with magnesium stearate and the corn starch andthe mixture is compressed into 225 mg tablets using an 11/32 inchstandard concave punch. Yield equals approximately 6000 tablets eachcontaining 2.5 mg of 5-oxo-2-pyrrolidinepropanoic acid.

Example 3

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      6      g                                             Lactose                  1268   g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid, lactose, and hydroxypropylcellulose are blended and granulated with 50:50 ethanol-water. The wetgranulation is screened, dried, and rescreened. The resulting driedgranulation is blended with magnesium stearate and the corn starch andthe mixture is compressed into 225 mg tablets using an 11/32 inchstandard concave punch. Yield equals approximately 6000 tablets eachcontaining 1.0 mg of 5-oxo-2-pyrrolidinepropanoic acid.

Example 4

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      300    g                                             Lactose                  974    g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid, lactose, and hydroxypropylcellulose are blended and granulated with 50:50 ethanol-water. The wetgranulation is screened, dried, and rescreened. The resulting driedgranulation is blended with magnesium stearate and the corn starch andthe mixture is compressed into 225 mg tablets using an 11/32 inchstandard concave punch. Yield equals approximately 6000 tablets eachcontaining 50.0 mg of 5-oxo-2-pyrrolidinepropanoic acid.

Example 5

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      250    g                                             Lactose                  1723   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 25.0 mg of5-oxo-2-pyrrolidinepropanoic acid.

Example 6

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      25     g                                             Lactose                  1948   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 2.5 mg of5-oxo-2-pyrrolidinepropanoic acid.

Example 7

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      10     g                                             Lactose                  1963   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 1.0 mg of5-oxo-2-pyrrolidinepropanoic acid.

Example 8

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      500    g                                             Lactose                  1473   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 50.0 mg of5-oxo-2-pyrrolidinepropanoic acid.

The invention is further illustrated by the following example of a 2gram rectal suppository. The suppository can contain a range of from 30mg to 500 mg of active ingredient.

Example 9

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      30     mg                                            Witepsol H35             1.97   g                                             ______________________________________                                    

The Witepsol H35 is melted by heating to 38° C.,5-oxo-2-pyrrolidinepropanoic acid is added and mixed until thoroughlydispersed and placed in a mold at 33°-34° C.

The invention is further illustrated by the following example of asuspension formulation. The suspension can contain a range of activeingredient from 50 mg/5 ml to 1 g/5 ml.

Example 10

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      10     g                                             Saccharin Sodium         0.5    g                                             Thihydroxysterain        0.75   g                                             Propylparaben            0.1    g                                             Imitation Cherry Flavor  2      ml                                            Neobee M-5 q.s. ad       100    ml                                            ______________________________________                                    

Propylparaben is dissolved in a portion of the Neobee M-5, thetrihydroxystearin is added and the mixture is homogenized for 30 minuteswhile maintaining the temperature between 50°-60° C. The mixture iscooled and the 5-oxo-2-pyrrolidinepropanoic acid, saccharin sodium andimitation cherry flavor are added. The volume is made up with NeobeeM-5.

The invention is further illustrated by the following example of Syrupfor Reconstitution. The syrup can contain between 50 mg/5 ml and 500mg/15 ml.

Example 11

    ______________________________________                                        Ingredient                Quantity                                            ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                       10     g                                            Sugar granulated, Bottlers grade                                                                        60     g                                            Artificial Peppermint Flavor, Water soluble                                                             0.4    g                                            (American Flavor and Fragrance)                                               Water q.s. ad             100    ml                                           ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid, granulated sugar, and artificialpeppermint flavor are dry blended. The blend is filled into 4 oz bottlewith a 100 ml calibration mark. At time of dispensing make up to volumewith water and shake until all solids are dissolved. The mixture isrefrigerated and used within 7 days.

The invention is further illustrated by the following Examples oftablets containing 1.0, 2.5, 25, 50 mg; capsules containing 1.0, 2.5,25, 50 mg respectively of active ingredient, an example of a parenteralformulation, an example of a Rectal Suppository formulation, aSuspension formulation, and a Syrup for Reconstitution formulation.

Example 12

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      150    g                                             benzyl ester                                                                  Lactose                  1124   g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid benzyl ester, lactose, andhydroxypropyl cellulose are blended and granulated with 50:50ethanol-water. The wet granulation is screened, dried, and rescreened.The resulting dried granulation is blended with magnesium stearate andthe corn starch and the mixture is compressed into 225 mg tablets usingan 11/32 inch standard concave punch. Yield equals approximately 6000tablets each containing 25.0 mg of 5-oxo-2-pyrrolidinepropanoic acidbenzyl ester.

Example 13

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      15     g                                             benzyl ester                                                                  Lactose                  1249   g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid benzyl ester, lactose, andhydroxypropyl cellulose are blended and granulated with 50:50ethanol-water. The wet granulation is screened, dried, and rescreened.The resulting dried granulation is blended with magnesium stearate andthe corn starch and the mixture is compressed into 225 mg tablets usingan 11/32 inch standard concave punch. Yield equals approximately 6000tablets each containing 2.5 mg of 5-oxo-2-pyrrolidinepropanoic acidbenzyl ester.

Example 14

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      6      g                                             benzyl ester                                                                  Lactose                  1268   g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid benzyl ester, lactose, andhydroxypropyl cellulose are blended and granulated with 50:50ethanol-water. The wet granulation is screened, dried, and rescreened.The resulting dried granulation is blended with magnesium stearate andthe corn starch and the mixture is compressed into 225 mg tablets usingan 11/32 inch standard concave punch. Yield equals approximately 6000tablets each containing 1.0 mg of 5-oxo-2-pyrrolidinepropanoic acidbenzyl ester.

Example 15

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      300    g                                             benzyl ester                                                                  Lactose                  974    g                                             Corn Starch              39     g                                             Hydroxypropyl cellulose  30     g                                             Magnesium stearate       7      g                                             Ethanol-water 50:50      qs                                                   ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid benzyl ester, lactose, andhydroxypropyl cellulose are blended and granulated with 50:50ethanol-water. The wet granulation is screened, dried, and rescreened.The resulting dried granulation is blended with magnesium stearate andthe corn starch and the mixture is compressed into 225 mg tablets usingan 11/32 inch standard concave punch. Yield equals approximately 6000tablets each containing 50.0 mg of 5-oxo-2-pyrrolidinepropanoic acidbenzyl ester.

Example 16

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      250    g                                             benzyl ester                                                                  Lactose                  1723   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 25.0 mg of5-oxo-2-pyrrolidinepropanoic acid benzyl ester.

Example 17

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      25     g                                             benzyl ester                                                                  Lactose                  1948   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 2.5 mg of5-oxo-2-pyrrolidinepropanoic acid benzyl ester.

Example 18

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      500    g                                             benzyl ester                                                                  Lactose                  1473   g                                             Magnesium stearate       27     g                                             ______________________________________                                    

The mixture is blended and filled into No. 4 hard gelatin capsules,filling each capsule with 200 mg of the powder mixture. Yield equalsapproximately 10,000 capsules each containing 50.0 mg of5-oxo-2-pyrrolidinepropanoic acid benzyl ester.

The invention is further illustrated by the following example of a 2gram rectal suppository. The suppository can contain a range of from 30mg to 500 mg of active ingredient.

Example 19

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      30     mg                                            benzyl ester                                                                  Witepsol H35             1.97   g                                             ______________________________________                                    

The Witepsol H35 is melted by heating to 38° C.,5-oxo-2-pyrrolidinepropanoic acid benzyl ester is added and mixed untilthoroughly dispersed and placed in a mold at 33°-34° C.

The invention is further illustrated by the following example of asuspension formulation. The suspension can contain a range of activeingredient from 50 mg/5 ml to 1 g/5 ml.

Example 20

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      10     g                                             benzyl ester                                                                  Saccharin Sodium         0.5    g                                             Trihydroxystearin        0.75   g                                             Propylparaben            0.1    g                                             Imitation Cherry Flavor  2      ml                                            Neobee M-5 q.s. ad       100    ml                                            ______________________________________                                    

Propylparabene is dissolved in a portion of the Neobee M-5, thetrihyroxystearin is added and the mixture is homogenized for 30 minuteswhile maintaining the temperature between 50°-60° C. The mixture iscooled and the 5-oxo-2-pyrrolidinepropanoic acid benzyl ester, saccharinsodium, and imitation cherry flavor are added. The volume is made upwith Neobee M-5.

The invention is further illustrated by the following example of a Syrupfor Reconstitution. The syrup can contain between 50 mg/5 ml and 500mg/15 ml.

Example 21

    ______________________________________                                        Ingredient               Quantity                                             ______________________________________                                        5-Oxo-2-pyrrolidinepropanoic acid                                                                      10     g                                             benzyl ester                                                                  Sugar granulated, Bottlers grade                                                                       60     g                                             Artificial Peppermint Flavor,                                                                          0.4    g                                             Water Soluble                                                                 (American Flavor and Fragrance)                                               Water q.s. ad            100    ml                                            ______________________________________                                    

The 5-oxo-2-pyrrolidinepropanoic acid benzyl ester, granulated sugar,and artificial peppermint flavor are dry blended. The blend is is filledinto 4 oz bottle with a 100 ml calibration mark. At time of dispensingmake up to volume with water and shake until all solids are dissolved.The mixture is refrigerated and used within seven days.

I claim:
 1. A compound having the structural formula ##STR13## wherein Ris selected from ##STR14## where R' is amino, alkylamino, ordialkylamino of from one to six carbon atoms.
 2. The compound defined inclaim 1 having the name of 5-oxo-2-pyrrolidinepropanoic acidN-4-(pyridinyl)amide.
 3. The compound defined in claim 1 having the nameof 5-oxo-2-pyrrolidinepropanoic acid 4-(3-aminopyridinyl)amide.
 4. Thecompound defined in claim 1 having the name of5-oxo-2-pyrrolidinepropanoic acid 3-(4-aminopyridinyl)amide.
 5. Apharmaceutical composition comprising an electroconvulsive shock-inducedamnesia reversing effective amount of a compound as defined by claim 1in combination with a pharmaceutically acceptable carrier.
 6. A methodfor reversing amnesia caused by electroconvulsive shock in a mammal inneed of said treatment, which method comprises administering to saidmammal the pharmaceutical composition defined in claim 5.